Antidote activity of vitamin B₁₂ derivative compared with its original and aqua forms; in vitro and in vivo study

Vitamin B₁₂ (VB12) - essential nutrient, required for detoxication of homocysteine, support of the myelinization in neural tissue and of the hematopoiesis. Certain drugs (such as antibiotics or antituberculosis drugs) result in deep deficiency of VB12. Using VB12 and its derivatives as antidotes is a promising direction in pharmacology, that allows compensation of the toxic effects of the drugs by nutraceuticals. In the present work, interactions of isoniazid (IZ) (a toxic drug, used in the pharmacotherapy of tuberculosis) with various VB12 derivatives were studied. An in vitro study in aqueous solutions with different pH values showed that the hydrophobic derivative of VB12-heptamethyl ester of aquacyanocobyric acid (ACm) promoted oxidation of IZ and contributed to reducing its hepatotoxicity. The effects of ACm were compared with VB12 and aquacobalamin in a rat model of acute IZ-induced hepatitis. IZ intoxication resulted in higher levels of aspartate aminotransferase (AST). Administration of VB12 and ACm normalized AST levels; treatment with aquacobalamin or ACm normalized total protein levels in blood serum. ACm malsoattenuated bilirubin levels in the blood. All VB12 derivatives significantly reduced lipid peroxidation, which was increased after IZ model was reproduced. Histological analysis confirmed the protective effects of these compounds on the rats' livers, kidneys, and brains: hepatocyte damage, inflammatory cell infiltration of liver tissues, acute ischemia of the renal cortex, and structural brain damage caused by IZ were all reduced. ACm had more positive effects on the liver than the other two compounds.